8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo(1,5-a)(1,4)benzodiazepine (Midazolam), a pre-operative anesthetic, belongs to a class of imidazobenzodiazepine compounds which are useful as anticonvulsants, sedatives, and muscle relaxants. Because of the therapeutic usefulness of these compounds, there is sustained interest in improving their synthesis, particularly the thermal decarboxylation step of the substituted tricyclic acid precursor.
U.S. Pat. No. 4,280,957, U.S. Pat. No. 4,440,685, U.S. Pat. No. 4,377,523, and GB 1,549,836 teach a high temperature decarboxylation of tricyclic acid to provide Midazolam, 8-chloro-6-(2-fluorophenyl)-1-methyl-6H-imidazo (1,5-a)(1,4)benzodiazepine (Isomidazolam) and decomposition by-products resulting from concomitant high temperature dehalogenation and dimerization of the tricyclic acid precursor. This method is impractical for large-scale preparation of Midazolam because of the costly chromatography equipment, plant time, and solvents required.
Attempts at improving the yield of Midazolam have focused on isomerizing purified Isomidazolam to Midazolam. U.S. Pat. No. 4,377,523 and U.S. Pat. No. 4,440,685 teach the isomerism of Isomidazolam to Midazolam by treatment of the former with potassium tert-butoxide in N,N-dimethylformamide (DMF) under kinetically controlled conditions. This method is also impractical for the large-scale syntheses of Midazolam because of the amount of thermal energy required for removal of the DMF.
Commonly owned, pending U.S. application Ser. No. 09/344280, filed Jun. 30, 1999, teaches isomerizing Isomidazolam to Midazolam in a lower-boiling solvent such as methanol, a solvent which is more easily removed than DMF. While this approach is an improvement over the art, there still remains a need in the pharmaceutical manufacturing industry for a lower temperature decarboxylation of imidazobenzodiadepines in general and tricyclic acid, in particular.